Several simple hollow tubes made of biosynthetic materials (i.e.,) polylactic-co-e-coprolactone, polyglycolide, collagen) are currently FDA-approved and have demonstrated clinical benefit in the repair of short nerve gaps. However, autografts remain the treatment of choice for nerve defects despite the need of donor nerve harvest and the associated morbidity of this procedure. In contrast to short gap injuries, autografts achieve minimal functional recovery for nerve defects longer than 30 mm and simple tubularization methods fail completely in repairing this critical gap. The regenerative failure of peripheral nerves through long-gaps seems to be due at least in part, to the lack of appropriate growth substrate and trophic support. We hypothesize that a growth factor strategy targeted to a broad cellular base in the regenerating nerves would be highly effective in achieving simultaneous cellularization, vascularization and nerve regeneration through long nerve gaps. A systematic evaluation of the trophic support needed for long-gap nerve repair, as well as the combination of increased regenerative area and pleiotrophic growth factor support is lacking. This study will address this need. In our preliminary studies, we have demonstrated that multiluminal nerve repair and pleiotrophic growth factors can successfully mediate nerve regeneration across a 30 mm gap. The overall goal of the proposed study will be focused on extending these results and systematically test the effect of neurotrophic factors (i.e., NGF and NT-3) alone or combined with PTN in long gap nerve repair. In Specific Aim 1 we will test the regenerative potency of combined Neurotrophin-Pleiotrophin treatment in vitro. In Specific Aim 2 we will evaluate the effect of neurotrophin/pleiotrophic growth factor support over long-gap nerve regeneration of the rabbit common personal nerve. This study is novel in that: 1) utilizes multicellular growth factors to stimulate both glial cellular proliferation and migration, and axonal regeneration, 2) uses collagen-suspended polymeric microparticles with encapsulated growth factors for controlled release, and 3) utilizes a recently developed multiluminal hydrogel nerve scaffold as biomimetic structural support. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants. PUBLIC HEALTH RELEVANCE: Implantable biosynthetic nerves are promising alternatives to autogenic nerve grafting, the standard of care for gap nerve injuries, due to their ability to mediate functional recovery without the need of sacrificing donor nerves or bearing the risk associated with tissue harvest morbidity. However, repairing critical gaps longer than 30 mm remains a formidable challenge. This research will contribute towards the elucidation of the structural and trophic support required to repair long gap nerve injuries trough biosynthetic nerve implants.